ABSTRACT Premature babies account for 10% of births in the United States; these newborn have immature lungs and often need help breathing at birth. Surfactant deficiency, immature antioxidant system and the need for extended mechanical ventilation support can cause damage to the lungs and other organs resulting in increased morbidity and mortality. Recent studies have shown that infants born <28 weeks? gestation had a higher risk of mortality when initially ventilated with 21% oxygen. The higher mortality was due to respiratory failure, which could be due to underdeveloped lungs, impaired oxygenation and impaired blood flow to the lungs. The Neonatal Resuscitation Program (NRP) developed by the American Academy of Pediatrics (AAP) provides guidelines for clinical treatment that sets target oxygen saturation goals. A recent study emphasized the importance of these target goals and failure to reach these targets by 5 min lead to higher mortality. The ancient practice of keeping the umbilical cord intact (attached to placenta) when a premature baby needs resuscitation could potentially help transition. In this proposal, we plan to study initiation of ventilation following preterm delivery in a fetal lamb model with low heart rate (<90/min), with 30% or 60% initial oxygen and titrate based on target oxygenation while the umbilical cord is still intact. We will compare this to resuscitation without an intact cord using similar initial oxygen concentration (30% or 60%). We will study the changes at transition by measuring oxygenation, pulmonary and cerebral blood flow and oxidative injury in these 4 groups. In this way, we can compare physiologic changes and the resultant oxidative stress markers to better understand what may be happening during the human preterm transition. Optimizing the initial oxygen exposure with an intact cord in a depressed preterm animal model examines this problem in a controlled way. Real-time continuous measurements of cerebral oximetry, systemic and pulmonary flow and pressure variations during the preterm transition will contribute to reducing morbidity and mortality in these babies. Relevance to current practice in neonatal resuscitation: Establishing good oxygen supply following birth is critical and it is more difficult to achieve with premature lung disease. Current AAP-NRP guidelines are vigilant to protect newborns from oxidative stress injury by targeting oxygen saturation ranges and limiting exposure to high oxygen concentrations. This newer approach examines physiology at birth in preterm lambs to establish optimal oxygen requirements with an intact umbilical cord to achieve the transition to air breathing with minimal oxidative damage.